ABSTRACT Ixodes ticks are vectors of many important human diseases including but not limited to Lyme disease, babesiosis, anaplasmosis, Borrelia miyamotoi disease, and tick-borne encephalitis causing viruses. Animals fed on by ticks may develop resistance to repeated tick feedings and individual humans have shown differing levels of resistance to tick feeding. While much has been learned about responses to ticks in model animals, recent studies have shown that ticks alter their salivary content based on the host they are feeding on and that immunological responses to tick bites can vary significantly between hosts. Human responses to tick bites have not been studied systematically due to the difficulty in obtaining consistent, characterizable samples. Our laboratories are involved in a multi-year study to examine the use of ticks as a device (xenodiagnosis) for detecting the persistence of the Lyme disease causing organism, Borrelia burgdorferi, after antibiotic treatment in patients. As a result, we have a large, well characterized collection of serum, plasma, whole blood and skin biopsy samples from around tick bite sites. Here, in response to a specific RFA (PAR-18-860) to study the Immune Response to Arthropod feeding, we propose to study human cellular and adaptive immune responses to tick bites and attempt to correlate specific components of each with resistance to tick feeding. In Aim 1, we will examine skin biopsy samples from patients where ticks fed either poorly or well to determine the cytokine profile in response to the bite using RNAseq. We will also determine the histological characteristics of the cellular infiltrate around the tick bite site. Using spatial transcriptomics, we will examine the cellular transcriptome as it relates to the tick bite site and understand the contribution of different cell types to the inflammatory milieu. In Aim 2, we will determine the impact of the adaptive immune response on tick feeding. Using artificial feeding membranes, we will test serum from patients who experienced good and poor feeding as well as the effects of the evolving immune response over time and after multiple exposures to ticks. At the completion of this project, we will have established the human immune correlates of successful and unsuccessful tick feeding which will form the building blocks for designing future approaches to preventing tick borne diseases through interfering with tick feeding.